The Jak/STAT signaling pathway is known to be activated in a number of cancers and inflammatory diseases. When activated through phosphorylation of a single tyrosine residue STAT3 dimerizes, translocates to nucleus, and serves as a transcription factor driving the upregulation of a number of proliferative and pro-survival genes including survivin, VEGF, Bcl-2, and Bcl-xL. These gene products are known to promote the growth and metastasis of over 20 tumor types and are also associated with the promotion of several proliferative skin disorders including psoriasis, T-cell lymphoma, and atopic dermatitis.
Inhibition of STAT3 phosphorylation in tumor bearing animals leads to the induction of apoptotic cell death and in preclinical orthotopic models of several diseases a significant reduction in tumor size. Likewise in inflammatory skin diseases inhibition of STAT3 phosphorylation leads to resolution of plaques, scales, and other associated lesions.
While the development of inhibitors of this pathway is currently desirable, a variety of inhibition (such as small molecule, antisense, iRNA) approaches have been tried with unsatisfactory results.